Recently, increasing attention has been devoted to photodynamic therapy (PDT) because of the discovery that many photosensitizer compounds, either naturally occurring or synthesized, exhibit remarkable anti-cancer and antiviral activities (Diwu et al., 1994, Pharmacol. Ther. 63:1-35).
Several studies have shown that benign hyperproliferative and hypervascular conditions such as psoriasis can be improved by photosensitization with porphyrins (Levy, 1994, Sem. Oncol. 21(6 Suppl. 15):4-10). Selective sensitization of psoriatic tissue using porphyrins has been demonstrated as an effective treatment for psoriasis and the efficacy of the treatment method may be related to the increased vascularity of psoriatic plaques (Stringer et al., 1996, J. Invest. Dermatol. 107:76-81). Another report using systemic tin-protoporphyrin in combination with long wavelength ultraviolet light suggests that this combination effects amelioration of psoriasis in psoriatic patients (Calzavara-Pinton et al., 1996, J. Photochem. Photobiol. B-Biol. 36:225-231).
One of the most commonly used regimens for the treatment of psoriasis, i.e. psoralen-ultraviolet A light (PUVA) treatment, is a form of PDT. PUVA treatment involves the administration to a patient of a psoralen compound, followed by illumination of the skin of the patient with light having a wavelength corresponding to ultraviolet A (UV-A) radiation. Although PUVA treatment provides relief from psoriasis, exposure of skin to UV-A radiation can have a number of undesirable effects, including a sunburn-like reaction and induction of skin tumors (Stern et al., 1997, New Eng. J. Med. 336:1090-1091).
Apart from the undesirable effects of UV radiation, psoralen, other furocoumarins such as 8-methoxypsoralen (8-MOP), and other types of photosensitizing agents such as hematoporphyrin derivatives, also have various disadvantages, including mutagenicity resulting from the ability of the compounds to intercalate into DNA, and toxicity of the compounds in patients.
Hypericin is a naturally occurring compound which is found in plants of the genus Hypericum, in insects of the genus Coccoidea, and in the ciliated protozoan Stentor coeruleus. Hypericin has been demonstrated to possess virucidal and antiviral activities (Lavie et al., 1989, Proc. Natl. Acad. Sci. U.S.A. 86:5963-5967; U.S. Pat. No. 4,898,891; U.S. Pat. No. 5,514,714; U.S. Pat. No. 5,506,271), and anti-tumor activities (Couldwell et al., 1994, Neurosurg. 35:705-710 [erratum appears in 1994, Neurosurgery 35:993]; Hamilton et al., 1996, J. Neurosurg. 85:329-334; Jarvis et al., 1994, Canc. Res. 54:1707-1714; Vandenbogaerde et al., 1996, Anticanc. Res. 16:1619-1625; Zhang et al., 1995, Canc. Lett. 96:31-35; Zhang et al., 1996, Neurosurg. 38:587-591).
Hypericin is maximally activated by visible light at wavelengths produced by a sodium lamp (590 nm) or cool white fluorescent light which significantly reduces the side effects associated with UV irradiation and permits deeper skin penetration. Hypericin has a relatively long half life (20-24 hours) which permits repeated light activation with single doses. This compound has been demonstrated in skin after systemic administration and it has been shown to be about 20% bioavailable following oral administration.
The photodynamic properties of hypericin have been described (Pace et al., 1941, J. Chem. Soc. 63:2570-2574)). Upon visible or UV light irradiation, hypericin in solution is capable of exciting oxygen to its singlet state and generating superoxide radicals, which can lead to oxidation of tryptophan imidazole groups in proteins, to oxidation of fatty acids in biological systems, or to other chemical reactions. Hypericin is maximally activated by light of about 570-650 nm wavelength, i.e. in the yellow region of the electromagnetic spectrum. Although hypericin has been known for many years, and although the application of non-photoactivated hypericin has been investigated in clinical studies of its anti-cancer and antiviral activities, very little is known about the mechanism of action of this compound at the biochemical or molecular level (Agostinis et al., 1995, Biochem. Pharmacol. 49:1615-1622). Photoreaction of hypericin has been demonstrated to produce singlet oxygen. In addition, there is evidence that hypericin inhibits protein kinase activity and thus, may exert its biological activity through pathways which are very different from, for example, psoralen (Song et al., 1979, J. Photochem. Photobiol. 29:1177-1197; Agostinis et al., 1995, Biochem. Pharmacol. 49:1615-1622). Furthermore, hypericin binds to phospholipids, such as cell membranes comprising phosphatidylcholine, and to retroviral particles, probably by associating with the lipid envelope thereof.
Photoactivation of hypericin prior to treatment therewith of an enveloped virus served to reduce the infectious titer of the enveloped virus, but did not inactivate the virus (Meruelo et al., U.S. Pat. No. 5,506,271). Exposure of hypericin to light has also been demonstrated to only slightly enhance hypericin's antiproliferative effects on glioma cells in vitro (Anker et al., 1994, Drugs Future 20:511-517). Hypericin has been reported to be incapable of inhibiting proliferation of leukemia cells (Jarvis et al., 1994, Canc. Res. 54:1707-1714). However, local illumination of the skin covering subcutaneously xenografted carcinoma cells in a nude mouse following intraperitoneal administration of hypericin to the mouse inhibited proliferation of these carcinoma cells (Vandenbogaerde et al., 1996, Anticanc. Res. 16:1619-1626). Lavie et al. (1995, Transfusion 35:392-400) demonstrated that photoactivated hypericin could be used to inactivate viruses in blood compositions in vitro, but reported no effect of hypericin on leukocytes. U.S. Pat. No. 5,514,714 (Meruelo et al.) discloses that administration of hypericin to a mammal can be effective to treat T-cell-mediated disorders. This reference did not investigate the use of photoactivated hypericin.
A long-felt need exists for photosensitizing agents which may be used to treat patients having a disorder, wherein the agent may be activated by non-UV light and wherein the combination of active agent and light is free of the deleterious side effects of known photosensitizing agents and UV light combinations.